The present invention relates generally to improved cathodes for use in an electrotransport device for delivering a beneficial agent (e.g., a drug), or for sampling an agent (e.g., a body analyte such as glucose) through a body surface of a patient. More particularly, the present invention relates to electrochemically reactive cathodes for an electrotransport device.
The term xe2x80x9celectrotransportxe2x80x9d refers generally to the delivery or extraction of an agent (charged, uncharged, or mixtures thereof through a body surface (such as skin, mucous membrane, or nails) wherein the delivery or extraction is at least partially electrically induced or aided by the application of an electric potential. The electrotransport process has been found to be useful in the transdermal administration of many drugs including lidocaine, hydrocortisone, fluoride, penicillin, and dexamethasone. A common use of electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine iontophoretically. The pilocarpine stimulates production of sweat. The sweat is then collected and analyzed for its chloride content to detect the presence of the disease.
Electrotransport devices generally employ two electrodes, positioned in intimate contact with some portion of the animal""s body (e.g., the skin). A first electrode, called the active or donor electrode, delivers the therapeutic agent (e.g., a drug) into the body. The second electrode, called the counter or return electrode, closes an electrical circuit with the first electrode through the animal""s body. A source of electrical energy, such as a battery, supplies electric current to the body through the electrodes. For example, if the therapeutic agent to be delivered into the body is positively charged (i.e., cationic), the anode is the active electrode and the cathode is the counter electrode to complete the circuit. If the therapeutic agent to be delivered is negatively charged (i.e., anionic), the cathode is the donor electrode and the anode is the counter electrode.
A widely used electrotransport process, electromigration (also called iontophoresis), involves the electrically induced transport of charged ions (e.g., drug ions) through a body surface. Another type of electrotransport, called electroosmosis, involves the trans-body surface (e.g., transdermal) flow of a liquid under the influence of the applied electric field. Still another type of electrotransport process, called electroporation, involves forming transiently existing pores in a biological membrane by applying high voltage pulses. In any given electrotransport system, one or more of these processes may occur simultaneously to some extent.
Most transdermal electrotransport devices have an anodic and a cathodic electrode assembly, each electrode assembly being comprised of an electrically conductive electrode in ion-transmitting relation with an ionically conductive liquid reservoir which in use is placed in contact with the patient""s skin. Gel reservoirs such as those described in Webster U.S. Pat. 4,383,529 are the preferred form of reservoir since hydrated gels are easier to handle and manufacture than liquid-filled containers. Water is by far the preferred liquid solvent used in such reservoirs, in part because many drug salts are watersoluble and in part because water has excellent biocompatability, making prolonged contact between the hydrogel reservoir and the skin acceptable from an irritation standpoint.
The electrodes used in transdermal electrotransport devices are generally of two types; those that are made from materials that are not electrochemically reactive and those that are made from materials that are electrochemically reactive. Electrochemically non-reactive electrodes, such as stainless steel, platinum, and carbon-based electrodes, tend to promote electrochemical oxidation or reduction of the liquid solvent at the electrode/reservoir interface. When the solvent is water, the oxidation reaction (at the anodic electrode interface) produces hydronium ions, while the reduction reaction (at the cathodic interface) produces hydroxyl ions. Thus, one serious disadvantage with the use of electrochemically non-reactive electrodes is that pH changes occur during device operation due to the water oxidation and reduction reactions which occur at the electrode/reservoir interfaces. Oxidation and reduction of water can largely be avoided by using electrochemically reactive electrodes, as discussed in Phipps et al. U.S. Pat. Nos. 4,747,819 and 5,573,503. Preferred electrochemically oxidizable materials for use in the anodic electrode include metals such as silver, copper and zinc. Of these, silver is most preferred as it has better biocompatability compared to most other metals. Preferred electrochemically reducible materials for use in the cathodic electrode include metal halides. Of these, silver halides such as silver chloride are most preferred. While these electrode materials provide an elegant solution to the problem of pH drift in the electrotransport reservoirs, they have their own set of problems.
The silver halide cathodes produce only halide (e.g., chloride) anions when they are electrochemically reduced (AgXxe2x86x92Ag+Xxe2x88x92) which anions are naturally present in the body in significant quantities. Thus, delivery of the chloride ions from the cathode into the patient creates no biocompatability problems. While the silver halide cathodes are quite biocompatible, they have serious disadvantages.
These disadvantages stem in part from the methods used to make the prior art silver halide cathodes. Generally, the prior art silver halide cathodes are made by one of several methods. In two of these methods, a silver foil is either reacted electrolytically with hydrochloric acid or dipped in molten silver chloride in order to form a silver chloride coating on the foil. Such coatings tend to have a limited thickness, thereby limiting the electrochemical capacity of such cathodes. Furthermore, coatings formed in either of these manners are prone to flaking off when the silver foil is flexed. A further disadvantage in connection with the electrolytic reaction of silver foil with hydrochloric acid is that it is a very slow process and not easily amenable to commercial manufacturing.
The third method of making prior art silver halide cathodes involves mixing silver halide particles into a binder, such as a polymeric matrix. This technique is described in Myers et al. U.S. Pat. Nos. 5,147,297 and 5,405,317. Because the polymeric binder is an electrically insulating material, these composite film electrodes also preferably have electrically conductive fillers such as carbon or metal particles, flakes or fibers. Typically, such composite cathodes comprise at least 20 vol. %, and more typically at least 40 vol. % of the inert polymeric binder. The polymeric binder and the conductive filler can create several problems in electrotransport drug delivery devices. For example, polymeric binders have a tendency to absorb drug (and/or other non-agent excipients in the electrolyte reservoir formulation such as anti-microbial agents) from the immediately adjacent electrolyte (i.e., donor or counter) reservoir. In some applications, binders in the donor electrode can absorb up to 50% of the agent in the donor reservoir. Such absorption is problematic because the absorbed agent is not delivered through the body surface causing insufficient therapy or the need to excessively load the reservoir with agent to compensate for such absorption. This means that excess drug and/or excipients may have to be loaded into the reservoir in order to compensate for the drug absorption by the electrode binder. This increases the total drug/excipient loading in the system and makes such systems more expensive, particularly with high cost drugs. Secondly, when the conductive filler is carbon or graphite, such materials have a very high affinity to organic compounds and thus there is a strong tendency for the drug in the adjacent drug reservoir to be adsorbed onto the surface of the conductive filler.
In addition, composite electrodes having more than 20 vol. % binder and typically more than 40 vol. % binder, are necessarily thicker and have lower discharge capacity, due to the inert nature of the binder. Electrode thickness is of particular concern since in recent years, electrotransport delivery devices have become much smaller, particularly with the development of miniaturized electrical circuits (e.g., integrated circuits) and more powerful lightweight batteries (e.g., lithium batteries). Added thickness is also undesirable because it takes away from other dimensional freedoms for system design, such as employing larger reservoirs, higher capacity thick batteries, more advanced and thicker electronic circuitry, biofeedback components, LCD displays, and other electronic components.
Another disadvantage with composite electrodes is that undesirable compounds can leach from the composite electrode into the adjacent drug or electrolyte reservoir and, possibly, onto or through the body surface. Such undesirable compounds may include impurities, residual solvent, unreacted monomer, dissolved binder, and the like. As a result, the presence of such compounds may deleteriously affect the biocompatability, efficacy and safety of the prior art electrotransport devices.
Still another disadvantage of the composite electrode is that hazardous materials (e.g., solvents) may be discharged into the environment when the electrode is manufactured. For example, silver chloride inks can be made by blending particulate silver chloride with polyisobutylene dissolved in a volatile organic solvent. The mixture is generally sprayed or roll coated onto a substrate and dried. Unless the overspray is filtered, scrubbed and burned, it is emitted into the atmosphere. Moreover, solvent is given off as the ink dries, which is difficult and expensive to capture. Thus, the environmentally hazardous materials used to process ink based and other polymeric electrodes are costly to recover.
Hence, there is a need for an improved electrode comprised of a reducible silver halide (such as silver chloride) to replace silver halide-coated silver foil electrodes and polymeric composite electrodes containing silver chloride particles, and to overcome the associated disadvantages thereof. There is also a need for an electrochemically reactive cathodic electrode having improved mechanical properties and cathodic discharge performance.
The present invention provides a cathodic electrode assembly for an electrotransport device adapted to deliver a therapeutic agent (e.g., a drug), or extract a body analyte (e.g., glucose) through a body surface such as skin. The cathodic electrode assembly includes a solid silver halide cathodic electrode. The cathodic electrode assembly also includes a cathodic electrolyte reservoir which is positioned adjacent and in ion-transmitting relation with the cathode. In use, the cathodic electrolyte reservoir is positioned intermediate the cathode and the body surface, and in ion-transmitting relation with the body surface.
The cathodic electrode is comprised of at least 95 vol. % silver halide, and preferably is comprised of substantially 100% silver halide. The cathode has an organic material content of less than 1 vol. % and preferably is substantially free of any organic materials such as binders, adhesives or other polymers. The cathodic electrode is also substantially free of any electrically conductive filler which can absorb materials contained in the electrolyte reservoir. A particularly preferred form of the silver halide cathodic electrode is substantially pure silver chloride foil having a thickness of 0.05 to 0.15 mm. In cases where the cathodic electrode is substantially pure silver chloride, the electrode preferably has an electrically conductive current collector positioned against a surface thereof.
The present invention also provides a method of making a cathodic electrode assembly for such an electrotransport delivery/sampling device. The method includes forming a solid silver halide cathodic electrode comprised of at least 95 vol. % silver halide and containing less than 1 vol. % organic materials and being substantially free of any electrically conductive filler which absorbs materials from the cathodic electrolyte reservoir. The electrode is then positioned against an electrolyte reservoir to form the electrode assembly. The electrode forming step can be performed by any number of techniques including (1) forging silver halide particles; (2) casting molten silver halide to form a sheet and then calendering the sheet to form a foil; (3) depositing a slurry of silver halide particles onto a screen, drawing off the liquid to form a silver halide sheet and calendering the sheet to form a foil; and (4) mixing silver halide particles in an organic binder, forming the mix into a sheet and then pyrolyzing the sheet to burn off the organic binder.
The present invention overcomes the disadvantages associated with composite electrodes and the prior silver chloride electrode layers. The electrodes of the present invention do not have the disadvantages associated with composite silver chloride electrodes, such as drug and/or excipient absorption, introduction of contaminants, unnecessarily great thickness, and solvent emission during the manufacturing process.